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The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N -alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis. [ABSTRACT FROM AUTHOR]

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t -butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections. [ABSTRACT FROM AUTHOR]

Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N , N -dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t -butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N -dealkylation liability observed for the previous lead. [ABSTRACT FROM AUTHOR]

Abstract: Orally bioavailable inhibitors of β-(1,3)-d-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. [Copyright &y& Elsevier]

Abstract: Objective: To test the role of ERβ in the control of estrogen-dependent thermoregulation in rats. Methods: Test the ability of an ERβ-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX). Results: ERβ-19 is a tetrahydrofluorenone ERβ-selective ligand that displaces 0.1nM estradiol from ERβ with an IC50 of 1.8nM compared to an IC50 of 141nM for ERα. Like estradiol, it acts as an agonist on ERβ-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERα-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERβ-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERβ-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERα. Thus, the ERβ-19 suppression of rat TST is mediated by ERβ without eliciting the activity of ERα. Conclusion: Estrogen-sensitive thermoregulation in ovariectomized rats can be controlled by an ERβ-selective ligand. [Copyright &y& Elsevier]

Abstract: Several tetrahydrofluorenones with a triazole fused across C7–C8 showed high levels of ERβ-selectivity and were found to be potent ERβ-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7nM affinity and 333-fold selectivity for ERβ. [Copyright &y& Elsevier]